Yersinia pestis, the causative agent of pneumonic and bubonic plague, has a high potential for use as a biological warfare or bioterrorism agent. The bacterium is easily cultured and genetically manipulated and can be delivered in aerosolized droplets. The resulting pneumonic plague has a short incubation time and is rapidly and highly fatal. Great potential exists for spread of pneumonic plague from primary infected individuals to their contacts. Currently, there is no available vaccine against pneumonic plague. Research from Dr. Straley's group has revealed two kinds of pathogenic mechanisms that potentially could function early in pneumonic plague. Contrary to reports in the literature, they have found that Y. pestis cells invade host epitheloid cells at significant rates. They have also found that Y. pestis possesses three quorum-sensing, or cell-density signaling systems. The roles of these two traits in the pathogenesis of pneumonic plague have not been investigated. In fact, relatively few studies of pneumonic plague have been performed. In the interest of identifying early targets for intervention in pneumonic plague, the applicant proposes to characterize host cell invasion and the three quorum-sensing systems in Y. pestis. The applicant will use a pneumonic plague mouse model to determine the roles of these traits in virulence. These studies should enhance understanding of the pathogenesis of pneumonic plague and facilitate the development of measures to protect people against possible bioterrorism based on Y. pestis. The proposed study is designed to have two lines of research running in parallel so as to gain maximal synergism from the collaboration of three research groups. The specific aims of this application are 1) to characterize the role of invasion in pneumonic plague and 2) to characterize the role of quorum sensing in pneumonic plague.